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The functions and regulation of the PTEN tumour suppressor: new modes and prospects

Nature Reviews Molecular Cell Biology volume 19, pages 547–562 (2018)Cite this article

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Abstract

PTEN is a potent tumour suppressor, and its loss of function is frequently observed in both heritable and sporadic cancers. PTEN has phosphatase-dependent and phosphatase-independent (scaffold) activities in the cell and governs a variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. Even a subtle decrease in PTEN levels and activity results in cancer susceptibility and favours tumour progression. Regulation of PTEN has therefore emerged as a subject of intense research in tumour biology. Recent discoveries, including the existence of distinct PTEN isoforms and the ability of PTEN to form dimers, have brought to light new modes of PTEN function and regulation. These milestone findings have in turn opened new therapeutic avenues for cancer prevention and treatment through restoration of PTEN tumour suppressor activity.

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Fig. 1: Structure and activity of PTEN.
Fig. 2: PTEN functions in the nucleus and the tumour microenvironment.
Fig. 3: Molecular mechanisms of PTEN regulation.
Fig. 4: Model of PTEN dimerization, activation and secretory regulation.

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Acknowledgements

The authors thank all the members of the Pandolfi laboratory for their constructive comments and L. Southwood and E. Stack for editing the manuscript. This work was supported by funding from the National Cancer Institute (R35CA197529 to P.P.P.) and the Department of Defense PCRP Postdoctoral Training award to Y.-R.L. and M.C.

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Nature Reviews Molecular Cell Biology thanks G.-S. Feng and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. These authors contributed equally: Yu-Ru Lee, Ming Chen

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  1. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Yu-Ru Lee, Ming Chen & Pier Paolo Pandolfi

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Y.-R.L., M.C. and P.P.P. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Pier Paolo Pandolfi.

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Glossary

PTEN hamartoma tumour syndromes

(PHTS). Encompass a spectrum of disorders caused by germline mutations of the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various organs. Hamartoma is a general term for a benign tumour-like malformation composed of mature cells in a tissue that has grown in a disorganized manner as a result of developmental defects.

Haploinsufficient

A situation in a diploid organism when one copy of a gene is inactivated due to mutation or deletion but the product of the remaining normal allele is not sufficient for normal cellular functional output (for example, suppression of tumorigenesis), resulting in an abnormal phenotype or diseased state (for example, tumour initiation).

PI3K–AKT–mTOR pathway

A central signalling pathway that integrates both extracellular and intracellular signals to control cellular metabolism, growth, proliferation, cancer and longevity. Its activation contributes to the pathogenesis of many tumour types. This pathway is antagonized by various factors and, notably, by PTEN.

Small-angle X-ray scattering (SAXS) analysis

A powerful technique used to study protein structure and interactions that is capable of delivering structural information in dimensions between 1 and 100 nm.

PEST (Pro, Glu, Ser, Thr) sequences

A peptide sequence that is rich in proline (P), glutamic acid (E), serine (S) and threonine (T). Proteins possessing this sequence display a short intracellular half-life. Therefore, it is hypothesized that this sequence acts as a signal peptide for protein degradation.

PDZ domain

A common structural domain of 80–90 amino acids that serves as a protein–protein interaction motif and is found in signalling proteins in bacteria, yeast, plants, viruses and animals.

Dual-specificity protein phosphatase

A phosphatase that can act on both tyrosine and serine/threonine residues.

Annexin 2

A Ca2+-regulated membrane protein and an F-actin-binding protein enriched at actin assembly sites on the plasma membrane and on endosomal vesicles. It is involved in diverse cellular functions, including cell motility and endocytosis.

Major vault protein

(MVP). Large multi-subunit ribonucleoprotein particle, which is considered to be a general carrier for nucleocytoplasmic transport.

RAN-GTPase

A GTP-binding protein involved in nucleocytoplasmic transport. It is required for the import of proteins into the nucleus and for RNA export.

Centromere

The part of a chromosome that links sister chromatids. The physical role of the centromere is to act as the site of assembly of the kinetochores — a highly complex multiprotein structure that is responsible for chromosome segregation.

Anaphase-promoting complex

(APC/C). Also known as the cyclosome. An E3 ubiquitin ligase that has a crucial function in the regulation of the mitotic cell cycle through targeting key mitotic regulators for degradation by the 26 S proteasome.

Dentate gyrus

A part of the hippocampus that is thought to contribute to the formation of new episodic memories, the spontaneous exploration of unknown environments and other functions.

β-catenin

A subunit of the cadherin protein complex that constitutes adherens junctions and a key downstream effector in the canonical WNT signalling pathway.

ETS2

A transcription factor that binds specifically to the DNA GGAA/T core motif in gene promoters and stimulates transcription of genes involved in development and apoptosis.

Senescence-associated secretory phenotype

(SASP). Effects mediated by the secretion of a range of proteins, including cytokines, chemokines and proteases by senescent cells. These effects are extremely diverse and include both autocrine and paracrine signalling, pro-tumorigenic and tumour-suppressive effects and pro-inflammatory and anti-inflammatory signalling.

Exosomes

Cell-derived vesicles that are present and secreted out of mammalian cells.

Competitive endogenous RNA

(ceRNA). A type of RNA that communicates with and regulates other RNA transcripts by competing for shared microRNAs.

Sporadic cancers

Cancers that occur in individuals who do not have a family history of that cancer or an inherited change in their DNA that would increase their risk of that cancer.

Cowden disease

An autosomal dominant multiple hamartoma syndrome that results most commonly from a mutation in the PTEN gene. The disease was named after the family in which it was first reported. Although the tumours are largely benign, individuals with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid and uterus.

ERK

A serine/threonine-specific protein kinase that is involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and pro-inflammatory cytokines. It regulates cellular functions, including proliferation, gene expression, differentiation, mitosis and cell survival.

Pseudogene

A genetic unit transcribed into non-coding RNA that has a counterpart in another gene from which it is derived. The expressed pseudogenes have promoters, CpG islands and splice sites, although some do not contain introns because they were generated from mRNA retrotransposition. Pseudogenes have often lost their ability to encode proteins, for which they are often referred to as ‘junk DNA’. They have now been functionally resurrected and attributed to a number of non-coding RNA functions, including their ability to act as competitive endogenous RNAs.

Nucleophile

A chemical species that can donate an electron pair to an electrophile to form a chemical bond in relation to a reaction.

Anchorage-independent cell growth

A type of growth where cells grow in the absence of a stable surface to which they can adhere. It is a key aspect of the neoplastic transformation, particularly with respect to metastatic potential.

Schwann cells

Cells in the peripheral nervous system that produce the myelin sheath around neuronal axons and function to support neurons. They are named after German physiologist Theodor Schwann, who discovered them in the 19th century.

Imaginal discs

Sac-like epithelial structures that are found inside the larvae of insects and become a portion of the outside of the adult insect after pupal transformation.

Sciatic nerve

The largest single nerve in humans and animals. It runs from each side of the lower spine through deep in the buttock into the back of the thigh and all the way down to the foot. It serves a vital role in connecting the spinal cord with the leg and foot muscles.

RHOA

A member of the RHO family of small GTPases, which function as molecular switches in signal transduction cascades. The RHOA protein promotes reorganization of the actin cytoskeleton and regulates cell shape, attachment and motility and is associated with cancer cell proliferation and metastasis.

β-arrestins

Multifunctional adaptor proteins that are best known for their ability to desensitize G protein-coupled receptors, thereby regulating a diverse array of cellular functions downstream of G protein-coupled receptors.

PTEN-induced putative kinase 1

(PINK1). A mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene. PINK1 activity triggers the binding of the parkin protein to depolarized mitochondria, in turn inducing mitophagy. Mutations in this gene result in autosomal recessive Parkinson disease.

Nucleolin

The major nucleolar protein of growing eukaryotic cells. This protein is associated with chromatin and pre-ribosomal particles and functions to regulate ribosomal RNA transcription and ribosome assembly.

Lipidoids

Any materials having characteristics of a lipid.

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Lee, YR., Chen, M. & Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19, 547–562 (2018). https://doi.org/10.1038/s41580-018-0015-0

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